Fragile X syndrome is a leading cause of mental retardation. The molecular basis of fragile X syndrome is the expansion of a trinucleotide repeat within the FMR1 gene, resulting in the absence of the encoded protein, FMRP. Although there has been a spectacular increase in the understanding of this disorder in recent years, much remains to be learned. To capitalize upon this trajectory of understanding, a well focused, multidisciplinary group effort to further elucidate the molecular basis of fragile X syndrome was initiated in September of 1997 with the funding of this program project composed of seven projects and one core. This revised proposal, in response to the formal review following three years of funded research, reflects a tighter, more thematic program of five interrelated and collaborative projects and one core at Emory University School of Medicine. These projects dramatically expand the scope of contemporary fragile X syndrome research and specifically address issues crucial for future investigation and intervention. A central program theme of FMRP expression and function cover the five broad, multidisciplinary projects. Project II will seek to understand the mechanistic details of chromatin changes leading to the transcriptional suppression of FMR1, the disease-causing consequence of full repeat expansion. Project I aims determine the biochemical and clinical consequences of smaller intermediate and premutation alleles that are found in 5% of the population. Projects V seeks to understand the biochemistry of FMRP with structure/function studies that are key in our continued understanding of the consequences of the absence of FMRP or a more subtle reduction of FMRP levels, studied in the prior two projects. Project III develops model systems where genetically modified mice and cell lines are produced where FMRP expression can be temporally and quantitatively controlled, both pre- and postnatally as well as in vitro. Along with the other projects, these novel biological resources will be used to explore new aspects of the pathophysiology of fragile X syndrome. This program of investigation into fragile X syndrome, by a highly interactive and multidisciplinary team with proven collaborative abilities, represents one of the largest research centers on this disorder in the world and aims to further our continued understanding of this important and common form of mental retardation.